One of the central issues of neuroscience concerns the mechanisms underlying the ability of the nervous system to respond to environmental stimuli that are both normal and traumatic. The neonatal superior cervical (sympathetic) ganglion (SCG) of the rat has been heavily scrutinized for its ability to alter its neurotransmitter complement in response to changing environmental signals. In one instance of dramatic neurotransmitter plasticity, substance P (SP) and the mRNA coding for its prohormone precursor are increased in the SCG when presynaptic electrical activity is withdrawn. Since the increase in SP occurs in the face of damage (i.e., deafferentation) to the ganglion, we sought to determine whether immune cytokines, released during injury, played a role in regulating the increase in SP. In preliminary studies we have found that interleukin-1 (IL-1) substantially increases SP and the mRNA coding for its prohormone precursor in cultured (injured) sympathetic ganglia; however, this is not a direct action of IL-1 on neurons, but rather involves the IL-1 induction of leukemia-inhibitory factor (LIF), ciliary neuronotrophic factor (CNTF), and possibly other molecules. These, in turn, work on neurons to effect the increase in SP. Because SP exerts a variety of stimulatory actions on the immune system, these data suggest a pivotal role for SP in mediating neuroimmunological communication in the periphery. Several issues raised by these findings are to be addressed in this proposal. Specifically, we plan to determine which cells bear the IL-1 receptor and which are the source of the intermediate molecules; whether IL-1 induces new biosynthesis of LIF and CNTF; whether the loss of presynaptic electrical activity causes neurons to elaborate IL-1; whether tumor necrosis factor-alpha, another SP-inducing macrophage product, operates through mechanisms similar to those of IL-1; whether the biosynthesis of neuropeptides other than SP is affected by IL-1; the role of IL-1-induced SP in promoting the survival and/or differentiation of sympathetic ganglia and/or in promoting immune activation.